BROSYM

Cefoperazone/sulbactam: empirical use for nosocomial infections

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Diversity of nosocomial pathogens

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醫學中心醫學中心醫學中心醫學中心

區域醫院區域醫院區域醫院區域醫院

台灣院內感染監視資訊系統(TNIS)(TNIS)(TNIS)(TNIS)

Regimens for nosocomial infections

� Broad-spectrum antibiotics� Ceftazidime, Cefepime

� Piperacillin/tazobactam� Carbapenems

� Quinolones

+/-� Anti-MRSA

+/-� Anti-anaerobes

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Current empirical therapy for nosocomial infection

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A.b.

Current empiricalbroad spectrum antibiotic

P.a.

P.a. S.a.S.a.

Anaerobes

Anaerobes

Anaerobes

A.b.A.b.

K.p.

K.p.

Carbapenem-resistant Acinetobacter baumannii: alway s multidrug resistant

5台灣院內感染監視資訊系統(TNIS)(TNIS)(TNIS)(TNIS)

Inappropriate therapy results in grave outcome for A. baumannii

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Lee YT, Chen TL, et al. CID 2012:55 209-215

Outline

� Background information of Brosym � Microbiology spectrum� Approved indications and guideline� Potential side effects.

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Product introduction

� 產品名：博益欣注射劑 Brosym for Injection� 成 分: Cefoperazone 500mg/Sulbactam 500mg� 規 格: 1g/vial (效價)� 類 別: 新複方新藥

� 健保價: 297元/vial

� 同成分同劑型藥品他國上市現況：� 複方製劑( Cefoperazone / Sulbactam )：

� 十大先進國：日本(1986年)

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The mechanism of Brosym

� Cefoperazone ( CPZ)� 3rd cephalosporin.� Inhibition of bacterial cell wall synthesis through binding on PBP. � Spectrum cover G(+) and G(-)，including Pseudomonas。

� Sulbactam ( SUL)� β-lactamase inhibitor.� Intrinsic activity against Acinetobacter, Bacteroides spp.

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Antimicrobial spectrum of CPZ/SUL

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Antimicrobial spectrum Summary of Spectrum

G(+) Staphylococcus spp. Most G(+),except MRSA, Enterococcus

G(-)

Including:E. coliCitrobacter spp.Klebsiella spp.Enterobacter spp.Serratia,Proteus spp.P. aeruginosaH. InfluenzaeAcinetobacter spp.

All important G(-), including P. aeruginosa and A. baumannii

(Except Stenotrophomonas maltophila)

Anaerobes Bacteroides All important anaerobes

(Except Clostridium species, but Clostridium perfringens is ok)

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Pathogens* NCPZ CPZ/SUL (1:1)

MIC50 MIC90 S (%) I (%) R (%) MIC50 MIC90 S (%) I (%) R (%)

Group A Streptococcus 39 0.125 0.25 100 0 0 0.25 0.5 100 0 0

Group B Streptococcus 102 0.25 0.5 100 0 0 0.25 0.5 100 0 0

MSSA 242 4 4 100 0 0 2 4 100 0 0

Streptococcus pneumoniae 93 2 8 100 0 0 2 8 100 0 0

Chiu CH et al. Unpublished data

Susceptibilities of some important Gram (+) pathogens: 2012

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�Isolates from NTUH, TVGH, CGMH, CMH, ChMH

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Pathogens* NCPZ CPZ/SUL

MIC50 MIC90 S (%) I (%) R (%) MIC50 MIC90 S (%) I (%) R (%)

E. coli 250 16 128 46.4 24.8 28.8 2 16 88 9.2 2.8

K. pneumoniae 231 2 128 64.9 7.4 27.7 0.5 32 84.8 9.1 6.1

P. mirabilis 174 2 128 76.2 10.8 13.1 1 8 95.4 3.5 0

S. marcescens 130 4 64 70.7 13.8 15.3 2 8 90 9.2 0.8

E. cloacae 178 2 128 76.4 7.3 16.3 1 16 84.8 14.6 0.6

Other Enterobacteriaceae 52 16 128 34.6 44.2 21.2 4 16 84.6 15.4 0

A. baumannii 375 >128 >128 0.27 5.1 94.7 8 64 71.2 17.6 11.2

P. aeruginosa 178 8 128 75.8 6.7 17.4 8 32 81.5 12.1 6.2

S. maltophilia 87 128 >128 5.8 4.6 89.7 64 128 20.7 12.6 66.7

Salmonella spp. 149 4 64 75.2 6.0 18.8 2 8 99.3 0.7 0

Chiu CH et al. Unpublished data

Susceptibilities of some important Gram (-) pathogens: 2012

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�Isolates from NTUH, TVGH, CGMH, CMH, ChMH

Susceptibilities of some important Gram (-) pathogens: 2009

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PIP/TAZ CPZ CPZ/SUL (1:1)

PIP/TAZ CPZ CPZ/SUL (1:1)

Pathogens N MIC90 (mg/L) Resistant (%)

ESBL (-) K. pneumoniae

50 16 64 4 2 10 0

ESBL (+) K. pneumoniae

50 64 >128 32 6 76 8

E. coli 50 32 16 8 2 4 2

E. cloacae 50 64 >128 32 6 36 2

S. marcescens 50 128 >128 32 12 42 6

P. aeruginosa 50 64 64 32 4 14 2

Imipenem-susceptibleA. baumannii

50 128 >128 16 10 64 0

Imipenem-resistant A. baumannii

50 >128 >128 32 76 100 8

S. maltophilia 50 >128 >128 32 96 64 30

Kuo HY et al. NEW MICROBIOLOGICA 2009; 32: 49-55

CPZ/SUL has lower resistant rate against A.baumannii than Amp/SUL

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ββββ-lactam/ββββ-lactamase Inhibitor Combinations against Acinetobacter baumannii

Resistant No. (%)

Ampicillin/sulbactam ( 2:1)

Cefoperazone/sulbactam ( 2:1)

Cefoperazone/sulbactam ( 1:1)

A. baumannii( IMP-susceptible )(N=68)

16 (23.5) 2 (2.9) 2 (2.9)

A. baumannii( IMP-resistant )(N=30)

9 (30) 5 (16.6) 3 (10)

1. Agar dilution2. Wang FD et al. Int J Antimicrob Agents 2004; 23: 590-595

15Journal of Clinical and Diagnostic Research. 2013 February, Vol-7(2): 224-228

CFP/SUL has low resistant rate in EU

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# #

# Resistant rate >70%

Outline

� Background information of Brosym � Microbiology spectrum� Approved indications and guideline� Potential side effects.

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Approved indications and dosage

� Upper and lower respiratory tract infections.

� Upper and lower urinary tract infections.

� Peritonitis , cholecystitis, cholangitis and other intra-abdominal infections.

� Pelvic inflammatory disease, endometritis, and other genitalia tract infection.

� Trauma, burn, surgical-site-associated infections.

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Population Suggested dosage

Adult •Severe infection: 4g, q12h

Pediatric • Severe infection:160mg/kg/day，• divided into 2-4 times /day

Design of TW phase III registration trial

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hospital-acquired pneumonia (HAP) and healthcare-associated pneumonia (HCAP)

• Comparative

• Randomized (1:1)

� 12 medical centers: 北榮、三總、雙和、萬芳、林長、、中山、奇美、成大、高長、高醫、高榮、義大

� 60位試驗(總/協同)主持人

試驗人數

Phase III study

Registration trial

Non-inferiority

designed

cefoperazone/ sulbactam: 4g q12h (8瓶/day)

cefepime ( Maxipime): 2g q12h ( 8瓶/day )

C+S cefepime total

Safety 79 87 166

Evaluable 66 81 147

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Phase III registration trial ( TW)

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Patient Population Hospital-acquired pneumonia and Healthcare-associated pneumonia

Patient no. 66 81

Regimens CPZ/SUL :4g q12h Cefepime: 2g q12h

Duration (d) of therapy 10.0± 2.9 10.6±3.0

Clinical response rate 81.8% 79%

Safety results in Taiwan pivotal trial

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CPZ/SBT (N=79) Cefepime (N=87)消化器官消化器官消化器官消化器官

腹瀉腹瀉腹瀉腹瀉 5 (6.3%) 2 (2.3%)嘔吐嘔吐嘔吐嘔吐 1 (1.3%) 1 (1.1%)便秘便秘便秘便秘 1 (1.3%) 0 (0%)

檢驗數值檢驗數值檢驗數值檢驗數值

AST、、、、ALT增加增加增加增加 2 (2.5%) 3 (3.4%)ALK-P增加增加增加增加 0 (0%) 1 (1.1%)PT、、、、APTT延長延長延長延長 2 (2.5%) 0 (0%)Eosinophil 增加增加增加增加 2 (2.5%) 0 (0%)血小板減少血小板減少血小板減少血小板減少 1 (1.3%) 0 (0%)高血鉀高血鉀高血鉀高血鉀 1 (1.3%) 0 (0%)低血鉀低血鉀低血鉀低血鉀 1 (1.3%) 1 (1.1%)

血液血液血液血液

貧血貧血貧血貧血 1 (1.3%) 0 (0%)其他其他其他其他

肝炎肝炎肝炎肝炎 0 (0%) 2 (2.3%)血尿血尿血尿血尿 1 (1.3%) 0 (0%)蛋白尿蛋白尿蛋白尿蛋白尿 0 (0%) 1 (1.1%)發汗發汗發汗發汗 0 (0%) 1 (1.1%)21

Summary of the Phase III bridging study

� The efficacy of cefoperazone/sulbactam was not inferior to cefepime in patients with HAP and HCAP.

� Cefoperazone/sulbactam was safe for patients with HAP and HCAP.

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Treatment recommendations for hospital acquired pneumonia (HAP) in Asia

Initial empirical antibiotic treatment for late ons et HAP

Potential pathogens Recommended antibiotic regimen

Streptococcus pneumoniaeHaemophilus influenzaeMSSAAntibiotic-sensitive enteric Gram-negative bacilli：：：：Escherichia coliEnterobacter speciesProteus speciesSerratia marcescens

MDR pathogensPseudomonas aeruginosaKlebsiella pneumoniae (ESBL)*Acinetobacter species*

Antipseudomonal cephalosporin (cefepime, ceftazidime)orAntipseudomonal carbepene (imipenem or meropenem)orβ-lactam/β-lactamase inhibitor (piperacillin-tazobactam)orCefoperazone/sulbactam+ Fluoroquinolone (ciprofloxacin or levofloxacin)orAminoglycoside (amikacin, gentamicin, or tobramycin)

Ampicillin/sulbactam (if sulbactam is not available)+ Fluoroquinolone (ciprofloxacin) or aminoglycoside

MRSA +/- linezolid or vancomycin†

Legionella pneumophila +/- azithromycin or fluoroquinolone＆

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Modified from Am J Infect Control 2008, Vol. 36 No. 4 Supp. 2, s83-92

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Treatment recommendations for HAP in Asia

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Am J Infect Control 2008;36:S83-92

對CRAB建議SUL劑量為≧6g/d

� Sulbactam: time-dependent

� i.v. 1g, T1/2~1hr, peak concentration 43mg/L

� 4g/day is inadequate to cover CRAB with MIC90: 32mg/L

� ≧6g/d of sulbactam is recommended

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IJAA ;2013:41:393–401

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CRAB感染病人的Brosym使用劑量

� 文獻顯示sulbactam須使用高劑量

� A case report of sulbactam 8g/day for MDR-Ab meningitis. No AE. Pharmacotherapy. 2002 Apr;22(4):527-32.

� Randomized study, sulbactam 9 or 12g/day for MDR-Ab VAP. No major AE. Scand J Infect Dis.2007;39(1):38-43.

� A prospective study, sulbactam 9g/day for MDR-Ab VAP. Comparable safe. Journal of Infection (2008) 56, 432-436.

• CCr>.60: 3g tid ( 9g/day)

• CCr 30~60: 2.25g tid ( 6.75g/day)

• CCr 7~30: 1.5g bid ( 3g/day)

� Brosym劑量 4g q8h ( 其中sulbactam為6g/day)

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CPZ/SUL + colistin has synergistic effect on MDR-Ab

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CPS: cefoperazon/ sulbactamCO: colistinRI: rifampicinIR: imipenem

ScienceAsia 40 (2014): 28–34

Colistin-based treatment for XDR-Ab pneumonia

CL � Inhaled colistin 40mg q6h� IV colistin 300mg loading followed by 150mg q12h

SB Sulbactam 6g/day (cefoperazone/sulbactam)

TC Tigecycline 100mg loading followed by 50mg q12h

CBHigh dose carbapenem prolonged infusion�Imipenem 1g over 3hr q8h�Meropenem 1g over 3hr q8h�Doripenem 1g over 4hr q8h

28International Journal of Antimicrobial Agents 43 2014; 378–382

Colistin-based treatment for XDR-Ab pneumonia

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CL+SB: 65%

CL+CB: 60%

CL+TC: 53%

International Journal of Antimicrobial Agents 43 2014; 378–382

Proposed guidelines for IAI in Asia

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International Journal of Antimicrobial Agents 30 (2007) 129–133

RCT for Intra-abdominal Infection

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• CPZ/SUL (2–8 g/day) • CAZ (2–6 g/day)-AMK (15 mg/kg/day)-MTZ

(500 mg q8h).

MASCOT Study Group et al. SURGICAL INFECTIONS 2008; 9, 367-376

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Overall results (IAI)

MASCOT Study Group et al. SURGICAL INFECTIONS 2008; 9, 367-376

CPZ/SUL CAZ+AMK+MTZ

Clinical outcome at 30-day follow up (CEE) 125/136 (91.9%) 108/132 (81.8%)

Clinical outcome at 30-day follow up (MITT) 134/154 (89.3%) 118/152 (79.2%)

Microbiologic outcomes (MEE) 65/71 (92.9%) 52/66 (80.0%)

Treatment-related adverse events 6.5% 16.4%

Discontinuations 12.3% 22.4%

European guidelines for empirical antibacterial the rapy for febrile neutropenic patients in the era of growing resistance

33Haematologica 2013; 98: 1826-1835

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European guidelines for empirical antibacterial the rapy for febrile neutropenic patients in the era of growing resistance

Haematologica 2013; 98: 1826-1835

Outline

� Background information of Brosym � Microbiology spectrum� Approved indications and guideline� Potential side effects.

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1. 改變會合成Vit. K的腸道菌

2. N-MTT (N-methylthiotetrazole) side chain: coumadin effect.

�Risks: malnutrition, hepatic and renal dysfunction, older age, and severity of illness, febrile neutropenia patient.

�Management:� 預防: 建議監測PT � 緊急: Vitamin K 10mg iv, FFP ( fresh frozen plasma)

Potential prothrombin time (PT) prolongation

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� A teaching hospital in Philadelphia from Feb. 1983 to Mar. 1986.

Incidence of hypoprothrombinemia & bleeding

Cefoperazone (374)

Ceftizoxime or cefotaxime (497)

Ceftazidime(476)

PT prolonged (>5s)

12.3% 5.8% 5.8%

Adjusted OR (95% CIs) = 3.6 (1.7-7.4) and 3.8 (1.8-7.8).

Risk of bleeding

Adjusted OR (95% CIs) = 1.1 (0.8-1.4) and 0.9 (0.6-1.2).

Strom BL et al. Pharmacoepidemiol drug saf 1999;8:81-94.

Avoid use of Brosym

� Liver function Child C� sepsis with DIC、

� Receiving heparin ( ex. Some hemodialysis patient)

� Taking warfarin:置換心臟機械瓣膜、心房顫動，深部靜脈栓塞的病人

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RCT for neutropenic fever

� Brosym 4g q8h is suggested for neutropenic fever patient.39

Eur. J. Clin. Microbiol. Infect. Dis., 1996, 15:625-634.

Clinical Infectious Diseases 1998;26:576–83.

Patient no. 174 175 101 102

›ANC <100/mm3 (%) 54% 54% 74% 82%

Regimens CPZ/SUL :2/1g q8h Imipenem:500mg, q6h

CPZ/SUL: 4/2g q12h

Imipenem:500 mg, q6h

Duration (d) of therapy NA NA 12 (3–69) 14 (3–50)

Clinical response rate 74% 73% 88 % 81%

Adverse events Diarrhea: 0.4%Nausea/vomiting: 0C. difficile infection:0

0%5.3%5%

Diarrhea: 31 (31%)

15 (15%)

Possible coagulopathy NA NA 10 (10%) 5 (5%)

hemorrhage NA NA 0 0

Note 10mg Vit. K once per week. Both, vancomycin 1g q12h

Both, 10mg Vit. K pre-therapy, and once per week.

Brosym PK parameters

CPZ SUL

T1/2 1.7hr ~2hr ~1hr

protein binding ~85% ~38%

代謝 幾乎不被代謝 幾乎不被代謝

排除75% 肝25% 腎 幾乎全為腎

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腎功能不佳時cefoperazone/sulbactam依文獻推論劑量(CPZ/SUL= 1:1)

1. Brosym 仿單

2. Pharmacotherapy. 2002; Apr 22 (4):527-32.

3. Scand J Infect Dis.2007;39(1):38-43.

4. Journal of Infection 2008; 56: 432-436.

5. Eur. J. Clin. Microbiol. Infect. Dis. 1996;15:625-634

6. Clinical Infectious Diseases 1998;26:576–83.

7. 2012 Guide to antimicrobial therapy in adult ICU Malaysian Society in Intensive Care

肌酸酐廓清率肌酸酐廓清率肌酸酐廓清率肌酸酐廓清率

(CCr，，，，mL/min)

CPZ/SUL參考劑量參考劑量參考劑量參考劑量

( other than CRAB and FN)

CPZ/SUL參考劑量參考劑量參考劑量參考劑量

( For CRAB and FN)

>30 4g, q12h1 4g, q8h 2-6

15~ 30 4g, q12h7 4g, q12h7

4141

CCr<15: 因此族群會有洗腎患者，當洗腎患者接受iv. Heparin後再使用Brosym會增加PT副作用，而各醫院對於洗腎患者是否IV給予heparin之操作不同。，因此為避免困擾，不建議CCr<15之患者使用Brosym。

Drug interaction

� 利尿劑（furosemide）: 與類似化合物(其他furosemide系藥劑)併用時會增強腎功能障礙。

� 酒精:飲酒有時因Disulfiram作用，會有顏部潮紅、噁心、心悸亢進、多汗、頭痛等發生，因此使用期間和使用過後至少一週內不能飲酒

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Summary of Brosym

� Broad antimicrobial spectrum which can cover most of the nosocomial pathogens including P. a. and A. b.

� Empirical therapy for nosocomial infection

� Dosage: Brosym 4g q12h.

� For CRAB infection or febrile neutropenia: 4g q8h is suggested.

� Multiple indications. � 上、下呼吸道感染、

� 上、下泌尿道感染、

� 腹膜炎、膽囊炎、膽管炎及其它腹腔內感染、

� 骨盆發炎、子宮內膜炎及其它生殖道感染、

� 創傷燙傷、手術後之二次感染。

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